Context. Current generation millimeter wavelength detectors suffer from scaling limits imposed by complex cryogenic readout electronics. These instruments typically employ multiplexing ratios well ...below a hundred. To achieve multiplexing ratios greater than a thousand, it is imperative to investigate technologies that intrinsically incorporate strong multiplexing. One possible solution is the kinetic inductance detector (KID). To assess the potential of this nascent technology, a prototype instrument optimized for the 2 mm atmospheric window was constructed. Known as the Néel IRAM KID Array (NIKA), it has recently been tested at the Institute for Millimetric Radio Astronomy (IRAM) 30-m telescope at Pico Veleta, Spain. Aims. There were four principle research objectives: to determine the practicality of developing a giant array instrument based on KIDs, to measure current in-situ pixel sensitivities, to identify limiting noise sources, and to image both calibration and scientifically-relevant astronomical sources. Methods. The detectors consisted of arrays of high-quality superconducting resonators electromagnetically coupled to a transmission line and operated at ~100 mK. The impedance of the resonators was modulated by incident radiation; two separate arrays were tested to evaluate the efficiency of two unique optical-coupling strategies. The first array consisted of lumped element kinetic inductance detectors (LEKIDs), which have a fully planar design properly shaped to enable direct absorbtion. The second array consisted of antenna-coupled KIDs with individual sapphire microlenses aligned with planar slot antennas. Both detectors utilized a single transmission line along with suitable room-temperature digital electronics for continuous readout. Results. NIKA was successfully tested in October 2009, performing in line with expectations. The measurement resulted in the imaging of a number of sources, including planets, quasars, and galaxies. The images for Mars, radio star MWC349, quasar 3C345, and galaxy M 87 are presented. From these results, the optical NEP was calculated to be around 1 × 10-15 W/Hz1/2. A factor of 10 improvement is expected to be readily feasible by improvements in the detector materials and reduction of performance-degrading spurious radiation.
A potential strategy to mitigate problems related to unproductive adsorption of enzymes onto lignin during the saccharification of lignocellulosic biomass is the addition of lignin-blocking agents to ...the hydrolysis reaction medium. However, there is a clear need to find more cost-effective additives for use in large-scale processes. Here, selected alternative low-cost additives were evaluated in the saccharification of steam-exploded sugarcane bagasse using a commercial enzymatic cocktail. The addition of soybean protein, tryptone, peptone, and maize zein had positive effects on glucose release during the hydrolysis, with gains of up to 36% when 8% (
w
/
w
) soybean protein was used. These improvements were superior to those obtained using bovine serum albumin (BSA), a much more expensive protein that has been widely reported for such an application. Moreover, addition of soybean protein led to a saving of 48 h in the hydrolysis, corresponding to a 66% decrease in the reactor operation time required. In order to achieve the same hydrolysis yield without the soybean additive, the enzyme loading would need to be increased by 50%. FTIR spectroscopy and nitrogen elemental analysis revealed that the additives probably acted to reduce unproductive binding of cellulolytic enzymes onto the lignin portion of the sugarcane bagasse.
Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. After diagnosis, patients with AML are mainly treated with standard induction chemotherapy combining cytarabine ...(araC) and anthracyclines. The majority of them achieve complete remission (CR) (65 - 80%). However, prospects for long-term survival are poor for the majority of patients. Resistance to chemotherapy therefore remains a major obstacle in the effective treatment of patients with AML. In this review, we highlight the current knowledge of substrate cycles involved in normal deoxynucleoside triphosphate (dNTPs) metabolism and their possible role in drug resistance to araC.
A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in
-mutant cancers is the acquisition of
reversion mutations that restore protein function. To estimate the prevalence ...of
reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic
mutations treated with the PARP inhibitor rucaparib.
reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (
= 0.049). Patients without
reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12;
< 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with
reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE:
reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple
reversion mutations, highlighting the ability to capture multiclonal heterogeneity.
.
While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to ...determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients.
Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001).
Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.
Nitric oxide (NO) is a molecule involved in several signal transduction pathways leading either to proliferation or to cell death. Induction of ornithine decarboxylase (ODC), the key enzyme of ...polyamine biosynthesis, represents an early event preceding DNA synthesis. In some cell types increased ODC activity seems to be involved in cytotoxic response. We investigated the role of NO and ODC induction on the events linked to cell proliferation or to cell death in cultured chick embryo cardiomyocytes. Exposure of cardiomyocytes to tumor necrosis factor (TNF) and lipopolysaccharide (LPS) caused NO synthase (NOS) and ODC induction as well as increased incorporation of 3H-thymidine. This last effect was blocked by a NOS inhibitor and was strongly reduced by difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. Sodium nitroprusside (SNP), an exogenous NO donor, inhibited the increases of NOS and ODC activities and abolished the mitogenic effect of TNF and LPS. Moreover, SNP alone caused cell death in a dose dependent manner. The cytotoxicity of SNP was not affected by DFMO while it was prevented by antioxidants. The results suggest that different pathways would mediate the response of cardiomyocytes to NO: they can lead either to ODC induction and DNA synthesis when NO is formed through NOS induction or to growth inhibition and cell death, when NO is supplied as NO donor. Increased polyamine biosynthesis would mediate the proliferative response of NO, while the cytotoxicity of exogenous NO seems to involve some oxidative reactions and to depend on the balance between NO availability and cellular redox mechanisms.
Aims.
In the presence of a sufficient amount of target material,
γ
-rays can be used as a tracer in the search for sources of Galactic cosmic rays (CRs). Here we present deep observations of the ...Galactic center (GC) region with the MAGIC telescopes and use them to infer the underlying CR distribution and to study the alleged PeV proton accelerator at the center of our Galaxy.
Methods.
We used data from ≈100 h observations of the GC region conducted with the MAGIC telescopes over five years (from 2012 to 2017). Those were collected at high zenith angles (58−70 deg), leading to a larger energy threshold, but also an increased effective collection area compared to low zenith observations. Using recently developed software tools, we derived the instrument response and background models required for extracting the diffuse emission in the region. We used existing measurements of the gas distribution in the GC region to derive the underlying distribution of CRs. We present a discussion of the associated biases and limitations of such an approach.
Results.
We obtain a significant detection for all four model components used to fit our data (Sgr A*, “Arc”, G0.9+0.1, and an extended component for the Galactic Ridge). We observe no significant difference between the
γ
-ray spectra of the immediate GC surroundings, which we model as a point source (Sgr A*) and the Galactic Ridge. The latter can be described as a power-law with index 2 and an exponential cut-off at around 20 TeV with the significance of the cut-off being only 2
σ
. The derived cosmic-ray profile hints to a peak at the GC position and with a measured profile index of 1.2 ± 0.3 is consistent with the 1/
r
radial distance scaling law, which supports the hypothesis of a CR accelerator at the GC. We argue that the measurements of this profile are presently limited by our knowledge of the gas distribution in the GC vicinity.
To determine patterns and predictors of concordance with institutional treatment guidelines among older women with breast cancer.
The study population included 1,568 patients aged 55 years and older ...who were treated at M.D. Anderson Cancer Center between July 1997 and January 2002 for stage I to IIIA invasive ductal and lobular breast cancer. Concordance with institutional guidelines was determined for definitive surgical therapy, radiotherapy after breast-conserving surgery, radiation therapy after mastectomy, adjuvant chemotherapy use, and adjuvant hormonal therapy use. The following variables were considered as possible modifiers of concordance: patient age, marital status, race, educational level, Eastern Cooperative Oncology Group performance status, comorbidity score, clinical stage, hormone receptor status, HER2-neu status, tumor grade, pathologic tumor size, lymphatic invasion, and number of lymph nodes involved. Logistic regression modeling was performed to determine the independent effect of each variable on guideline concordance.
Older women were less likely to receive treatment in concordance with guidelines for definitive surgical therapy (P < .001), postlumpectomy radiation (P = .03), adjuvant chemotherapy (P < .001), and adjuvant hormonal therapy (P < .001). In multivariate analysis, age > or = 75 years predicted a deviation from guidelines for definitive surgical therapy, adjuvant chemotherapy, and adjuvant hormonal therapy. Nonwhite race was associated with decreased likelihood of adjuvant radiation therapy after breast conservation.
After adjustment for comorbidity score, race, marital status, educational status, clinical stage, and tumor characteristics, increasing patient age was independently associated with decreased guideline concordance for definitive surgery, adjuvant chemotherapy, and adjuvant hormonal therapy. Future research should focus on delineating the possible reasons for guideline discordance.
The clinical impact of the positivity of the Deauville scale (DS) of positron emission tomography (PET) performed at the end of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients ...with advanced Hodgkin lymphoma (HL), in terms of providing rationale to shift poor responders onto a more intensive regimen, remain to be validated by histopathology.
This prospective trial involved patients with stage IIB/IV HL who after six ABVD cycles underwent PET (PET6) and core-needle cutting biopsy (CNCB) of 2-deoxy-2F-18 fluoro-d-glucose (FDG)-avid lymph nodes. Patients received high-dose chemotherapy/autologous haematopoietic stem cell rescue (HDCT/AHSCR) if CNCB was positive for HL, alternatively, if CNCB or PET was negative, received observation or consolidation radiotherapy (cRT) on residual nodal masses, as initially planned. The end-point was 5-year progression-free survival (PFS).
In all, 43 of the 169 (25%) evaluable patients were PET6 positive (DS 4, 32; DS 5, 11). Among them, histology showed malignancy (HL) in 100% of DS 5 scores and in 12.5% of DS 4 scores. Fifteen patients with positive biopsy received HDCT/AHSCR, whereas 28 patients with negative biopsy, as well as 126 patients with negative PET6, continued the original plan (cRT, 78 patients; observation, 76 patients). The 5-year PFS in the negative PET6 group, negative biopsy group and positive biopsy group was 95.4%, 100% and 52.5%, respectively.
DS positivity of end-of-ABVD PET in advanced HL carried a certain number of CNCB-proven non-malignant FDG-uptakes. The DS 4 scores which were found to have negative histology appeared to benefit from continuing the original non-intensive therapeutic plane as indicated by the successful outcome in more than 95% of them by obtaining similar 5-year PFS to the PET6-negative group. By contrast, the DS 5 score had consistently positive histology and was associated with unsuccessful conventional therapy, promptly requiring treatment intensification or innovative therapeutic approaches.
•Deauville score (DS) 4 at the end-of-ABVD FDG-PET in advanced Hodgkin lymphoma (HL) had a rate of negative-histology of 87.5%.•DS 5 score at the end-of-ABVD FDG-PET in advanced HL had a rate of positive-histology of 100%.•Histology is needed to confirm malignancy for DS 4 scores at restaging PET.•Switch to treatment intensification or innovative therapeutic approach as soon as possible for DS 5 score at restaging PET.
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